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<p>Microglia’s role in epilepsy through neuroimmune communication is poorly understood. Mechanisms by which neurons activate microglia and how microglia affect neuronal activity to drive seizure-related inflammation remain unclear. Here, we elucidated a crucial axis connecting pathological adenosine triphosphate (ATP) release induced by epileptiform neuronal activity to microglial MEF2A-dependent hyperactivation, which exacerbates epilepsy pathology. In epilepsy models, seizures cause excessive ATP release, activating microglial P2X7 receptors, causing CAMKII phosphorylation. This triggers HDAC5 translocation, freeing MEF2A for acetylation, and enhancing transcription. Acetylated MEF2A increases CD74 and NEK7 expressions, enhancing NLRP3 inflammasome activation and microglial hyperactivation, worsening neuronal hyperexcitability by increasing inhibitory synapses clearance. Targeting microglial MEF2A with parecoxib or AAV knockdown reduced seizure severity and cognitive deficits and maintained synaptic inhibition by reducing excessive microglial phagocytosis. This reveals an ATP-P2X7-Ca<sup>2</sup>⁺- MEF2A signaling axis connecting neuronal injury with pathogenic microglial activation, suggesting MEF2A as a therapeutic target for microglial-neuronal homeostasis restoration in epilepsy pathology.</p><p></p>

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Targeting MEF2A suppresses microglial hyperactivation and synaptic phagocytosis to attenuate epilepsy pathogenesis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月22日

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  • Jingheng Wu,
  • Jiayuanyuan Fu,
  • Shuai Wang,
  • Yuzhang Wu,
  • Xu Wang,
  • Shangang Feng,
  • Qi Shi,
  • Yuhao Wang,
  • Yetong Shi,
  • Yehong Fang,
  • Yu Lan,
  • Qiaoli Wu,
  • Chuan Du,
  • Shaoya Yin,
  • Lixia Xu,
  • Hua Yan

摘要

Microglia’s role in epilepsy through neuroimmune communication is poorly understood. Mechanisms by which neurons activate microglia and how microglia affect neuronal activity to drive seizure-related inflammation remain unclear. Here, we elucidated a crucial axis connecting pathological adenosine triphosphate (ATP) release induced by epileptiform neuronal activity to microglial MEF2A-dependent hyperactivation, which exacerbates epilepsy pathology. In epilepsy models, seizures cause excessive ATP release, activating microglial P2X7 receptors, causing CAMKII phosphorylation. This triggers HDAC5 translocation, freeing MEF2A for acetylation, and enhancing transcription. Acetylated MEF2A increases CD74 and NEK7 expressions, enhancing NLRP3 inflammasome activation and microglial hyperactivation, worsening neuronal hyperexcitability by increasing inhibitory synapses clearance. Targeting microglial MEF2A with parecoxib or AAV knockdown reduced seizure severity and cognitive deficits and maintained synaptic inhibition by reducing excessive microglial phagocytosis. This reveals an ATP-P2X7-Ca2⁺- MEF2A signaling axis connecting neuronal injury with pathogenic microglial activation, suggesting MEF2A as a therapeutic target for microglial-neuronal homeostasis restoration in epilepsy pathology.